The present invention relates to a fused heterocyclic ring derivative acting to enhance the action of cell differentiation inducing factors such as bone morphogenetic protein and neurotrophic factors, and possessing anti-matrix metalloprotease (MMP) activity, a method of its production, and use thereof.
Osteoporosis is a pathologic state or disease involving some symptom or risk due to quantitative reduction in bone exceeding a certain degree. Major symptoms are spinal kyphosis, and fractures of dorsolumbar bones, vertebral centra, femoral necks, lower end of radius, ribs, upper end of humerus, and others. In bone tissue, osteogenesis and bone destruction by bone resorption are repeated with a good balance (bone remodelling); osteoblasts and osteoclasts play key roles in osteogenesis and bone resorption, respectively. Bone resorption surpassing osteogenesis, upon deterioration of the balance between osteogenesis and bone destruction by bone resorption, results in osteoporosis with a quantitative reduction in bone. Traditionally, bone resorption suppressors such as estrogens, calcitonin and bisphosphonates have been mainly used as prophylactic/therapeutic drugs for osteoporosis. However, these bone resorption suppressors fail to have a satisfactory effect in some cases, due to limitation on the subject or to uncertain efficacy. There is therefore a need for an osteogenesis promoter that serves as a prophylactic/therapeutic drug for osteoporosis to increase once-decreased bone mass.
Bone morphogenetic protein (BMP), isolated from decalcified bone, is the only group of protein factors known to be capable of ectopic bone induction. It is therefore useful as an osteogenesis promoter in bone healing, bone reconstruction etc. Also, because BMP directly promotes osteoblast differentiation, it is assumed to play a role as a coupling factor in bone remodelling, and is thought to be closely involved in bone metabolism. Also, it is known that the BMP content in bone matrix in aged animals has been considerably decreased, suggesting that BMP is profoundly involved in the maintenance of bone mass. This suggests that BMP is promising as a therapeutic drug for various bone diseases such as osteoporosis. However, because BMP is normally present in trace amounts in living body so that its supply is limited, and because BMP is a protein so that a problem arises in its administration, the target diseases to which it is. applicable are limited.
In addition, BMP has been reported to possess an activity like that of neurotrophic factors [Journal of Cell Biology, Vol. 119, p. 1,721 (1992)]. Also, because it is known that the BMP gene is strongly expressed in brain tissue, and because BMP has been suggested as playing an important role in neural tube formation in embryogenesis, BMP is thought to be profoundly involved in the differentiation or functional maintenance of nerve cells.
Neurotrophic factors, a group of proteinous factors playing an important role in the survival and functional expression of nerve cells, include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). NGF promotes the differentiation and maturation of the sympathetic ganglion cells and dorsal spinal root ganglion cells of the neural tube in the peripheral nervous system and acts on the cholinergic neuron cells of the septal field (procephalic basal ganglia) in the central nervous system. NGF is essential for the maintenance of nervous function even after completion of ferentiation. BDNF acts on the dorsal spinal root ganglion cells and nodal ganglion cells in the peripheral nervous system but does not act on sympathetic ganglion cells. On the other hand, in the central nervous system, BDNF acts on the cholinergic nerve cells and GABA (xcex3-aminobutyric acid)-acting nerve cells of the septal field, and the dopaminergic nerve cells of the mesencephalon. NT-3 is characterized by potent action on the sensory nerve cells derived from the neural plate, although its action overlaps those of NGF and BDNF in the peripheral nervous system.
Alzheimer dementia has been characterized by extensive disorder and loss of cerebral cortical nerve cells, as well as degeneration and loss of cholinergic neuron of basal forebrain, including the septum; NGF and new neurotrophic factors are considered as candidates for therapeutic drugs therefore. Also, for Parkinson""s disease, a disease characterized by degeneration and loss of the mesencephalic dopaminergic nerve neuron, BDNF and GDNF (glial cell line-derived neurotrophic factors), neurotrophic factors for those nerve cells, are expected to serve as a therapeutic drug. Because these neurotrophic factors are proteins, however, their application are subject to limitation.
Osteoarthritis, a non-inflammatory disease based on articular cartilage degeneration, is irreversible and progressive, although its progression is slow. Spinal intervertebral degeneration is relatively common among males, while the incidence of knee joint degeneration is relatively high in females. Etiologically, systemic factors such as genetic predispositions, age, estrogen and obesity, and the local factor of mechanical load are involved. When articular cartilage begins to be destroyed by various causes, proteolytic enzymes, mainly metalloprotease and serine protease, are locally produced, whose action causes cartilage matrix lysis, resulting in cartilage cracking, abrasion, ulcer etc., which in turn lead to the exposure of the subcartilaginous plate and sometimes cause calcium pyrophosphate crystal deposition on the deformed articular cartilage surface. Clinical symptoms include pain, hydrarthrosis, limitation of range of joint motion, creaking sound and deformation. Although much remains unknown as to the mechanism of onset, it is known that production of collagenase and other matrix metalloproteases (MMPs) is induced by the cytokines produced by chondrocytes, macrophages and synovial cells, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-xcex1, resulting in the collapse of articular cartilage. Drugs that inhibit the metalloprotease production induction by these cytokines are therefore expected to be effective as prophylactic/therapeutic drugs for osteoarthritis; however, there are no known drugs with such action, and conventional chemotherapies comprise nothing more than symptomatic therapies such as oral or topical administration of sedative anti-inflammatory drugs, and intra-articular injection of articular cartilage-protecting drugs such as aqueous solutions-of hyaluronic acid.
The present invention provides a compound that enhances the action of cell differentiation induction factors, represented by BMP and neurotrophic factors, that is effective in the treatment and prevention of osteoporosis, bone fractures, and diseases based on nerve degeneration, such as Alzheimer""s disease, cerebral vascular dementia, amyotrophic lateral sclerosis (Lou Gehrig disease), depression and diabetic peripheral neuropathy, that possesses anti-MMP activity, and that is effective in the treatment and prevention of diseases involved by MMP, such as osteoarthritis, rheumatoid arthritis, arteriosclerosis and cancer metastasis.
After extensive investigation in search of low-molecular compounds that enhance the action of cell differentiation induction factors, the present inventors found that the fused thiophene derivatives represented by general formulas (I) and (Ixe2x80x2) below specifically enhance the osteoblast and nerve cell differentiation by BMP and neurotrophic factors, and suppress the collagenase production by chondrocytes. The present inventors made further investigation based on this finding, and developed the present invention.
Accordingly, the present invention relates to:
(1) a compound represented by general formula (Ixe2x80x2): 
wherein X represents a sulfur atom or an oxygen atom; Y represents an optionally oxidized sulfur atom or an oxygen atom; Z represents a bond or a divalent hydrocarbon group; R1 represents an optionally substituted hydrocarbon group; R2 represents an optionally amidated or esterified carboxyl group; ring A represents an optionally substituted aromatic 5-membered heterocyclic ring; provided that when X and Y are both S, 
does not represent 
(R represents a hydrogen atom or a C1-6 alkyl group); or a salt thereof,
(2) the compound according to term (1) above wherein Y is a sulfur atom,
(3) the compound according to term (1) above wherein Z is a bond,
(4) the compound according to term (1) above wherein R1 is a C1-8 alkyl group, a C6-10 aryl group or C7-14 aralkyl group,
(5) the compound according to term (1) above wherein R2 is a carboxyl group, a C1-8 alkoxy-carbonyl group, a carbamoyl group, an N-(C1-8 alkyl)carbamoyl group, an N-[di(C1-6 alkoxy)phosphoryl-C1-6 alkylphenyl]carbamoyl group or an N-(C1-8 alkyl), N-(C1-8 alkoxy)carbamoyl group,
(6) the compound according to term (1) above wherein R2 is a carboxyl group, a carbamoyl group or an N-(C1-8 alkyl)carbamoyl group,
(7) the compound according to term (1) above wherein ring A is an optionally substituted thiazole ring, oxazole ring, imidazole ring or thiophene ring,
(8) the compound according to term (1) above wherein ring A is (i) a thiazole ring, oxazole ring or imidazole ring which may be substituted with a C1-8 alkyl group, a C6-10 aryl group or a C6-10 aryl-C2-4 alkenyl group, or (ii) a thiophene ring which may be substituted with a carboxyl group, a C1-8 alkoxy-carbonyl group, a carbamoyl group, an N-(C1-8 alkyl)carbamoyl group, an N-[di(C1-6 alkoxy)phosphoryl-C1-6 alkylphenyllcarbamoyl group or a C6-10 aryl group,
(9) the compound according to term (1) above wherein ring A is (i) a thiazole ring, oxazole ring or imidazole ring substituted with a C1-8 alkyl group, a C6-10 aryl group or a C6-10 aryl-C2-4 alkenyl group, or (ii) a thiophene ring substituted with a C1-8 alkoxy-carbonyl group,
(10) the compound according to term (1) above wherein ring A is a thiazole ring or oxazole ring substituted with a C1-8 alkyl group or a C6-10 aryl group,
(11) the compound according to term (1) above wherein X is a sulfur atom or an oxygen atom, Y is a sulfur atom, Z is a bond, R1 is a C1-6 alkyl group, a C6-10 aryl group or a C7-14 aralkyl group, R2 is a carboxyl group, a C1-8 alkoxy-carbonyl group, a carbamoyl group, an N-(C1-6 alkyl)carbamoyl group, an N-[di(C1-6 alkoxy)phosphoryl-C1-6 alkylphenyllcarbamoyl group or an N-(C1-8 alkyl), N-(C1-8 alkoxy)carbamoyl group, ring A is (i) a thiazole ring, oxazole ring or imidazole ring substituted with a C1-8 alkyl group, a C6-10 aryl group or a C6-10 aryl-C2-4 alkenyl group, or (ii) a thiophene ring substituted with a C1-8 alkoxy-carbonyl group,
(12) the compound according to term (1) above which is 4,5-dihydro-8-methylthio-2-phenylfuro[3,4-e]benzothiazole-6-carboxylic acid, 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-e]benzothiazole-6-carboxamide, 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxamide, 4,5-dihydro-8-isopropylthio-2-methylthieno(3,4-g]benzoxazole-6-carboxamide, N-ethyl-4,5-dihydro-8-methylthio-2-phenylthieno(3,4-e]benzothiazole-6-carboxamide, N-(3,4-methylenedioxybenzyl)-4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxamide, N-(4-pyridylmethyl)-4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxamide, N-(3-pyridyl)-4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxamide, N-methoxy-N-methyl-4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxamide, or a salt thereof,
(13) a compound of the formula (Ixe2x80x3): 
wherein X represents a sulfur atom or an oxygen atom; Y represents an optionally oxidized sulfur atom or an oxygen atom; Z represents a bond or a divalent hydrocarbon group; R1 represents an optionally substituted hydrocarbon group; R2 represents an optionally amidated or esterified carboxyl group; ring A represents an optionally substituted aromatic 5-membered heterocyclic ring; but excluding the compound 
(14) a pharmaceutical composition which comprises an effective amount of the compound according to term (1) above and a pharmaceutically acceptable salt,
(15) the pharmaceutical composition according to term (14) above which is for prophylaxis or treatment of osteoporosis, bone fractures, osteoarthritis, rheumatoid arthritis, arteriosclerosis, cancer metastasis or a disease based on neural degeneration,
(16) an anti-matrix metalloprotease agent which comprises a compound represented by general formula (I): 
wherein X represents a sulfur atom or an oxygen atom; Y represents an optionally oxidized sulfur atom or an oxygen atom; Z represents a bond or a divalent hydrocarbon group; R1 represents an optionally substituted hydrocarbon group; R2 represents an optionally amidated or esterified carboxyl group; ring A represents an optionally substituted aromatic 5-membered heterocyclic ring; or a salt thereof,
(17) an enhancer for cell differentiation induction factor action containing the compound according to term (1) above,
(18) use of a compound of the formula (I) for manufacturing a pharmaceutical composition,
(19) a method which comprises administering an effective amount of a compound of the formula (I) in a pharmaceutically acceptable carrier to provide a prophylactic or therapeutic action for osteoporosis, fracture, osteoarthritis, rheumatoid arthritis, arterial sclerosis, cancer transfer or a disease based on degenerative nerve in warm blooded animals, and
(20) a method of producing a compound represented by the general formula: 
wherein Q represents a sulfur atom, an oxygen atom or NH; A1 represents a hydrogen atom or an optionally substituted hydrocarbon group; X represents a sulfur atom or an oxygen atom; Y represents an optionally substituted sulfur atom or an oxygen atom; Z represents a bond or a divalent hydrocarbon group; R1 represents an optionally substituted hydrocarbon group; R2 represents an optionally amidated or esterified carboxyl group; or a salt thereof, which comprises reacting a compound represented by the general formula: 
wherein Hal represents a halogen atom; and the other symbols have the same definitions as those shown above; or a salt thereof; with a compound represented by the general formula: 
wherein the symbols have the same definitions as those shown above; or a salt thereof.
With respect to general formulas (I), (Ixe2x80x2) and (Ixe2x80x3) [hereinafter together referred to as general formula (I)], X represents a sulfur atom (S) or an oxygen atom (O).
With respect to general formula (I), Y represents a sulfur atom that may be oxidized (S, SO, SO2) or an oxygen atom (O). Y is preferably a sulfur atom.
With respect to general formula (I), Z represents a bond or a divalent hydrocarbon group. Examples of divalent hydrocarbon groups include, for example, saturated or unsaturated divalent hydrocarbon groups having 1 to 3 carbon atoms, such as xe2x80x94(CH2)nxe2x80x94 (n represents an integer from 1 to 3), xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1CCH2xe2x80x94 and xe2x80x94CH2Cxe2x89xa1Cxe2x80x94 (e.g., alkylenes, alkenylenes, alkynylenes). Z is preferably a bond.
With respect to general formula (I), the hydrocarbon represented by R1, which may be substituted, is exemplified by aliphatic hydrocarbon groups which may be substituted, alicyclic hydrocarbon groups which-may be substituted, alicyclic-aliphatic hydrocarbon groups which may be substituted, aromatic hydrocarbon groups which may be substituted, and aromatic-aliphatic hydrocarbon groups (aralkyl groups) which may be substituted. Such aliphatic hydrocarbon groups include saturated aliphatic hydrocarbon groups (e.g., alkyl groups) having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl and octyl; and unsaturated aliphatic hydrocarbon groups (e.g., alkenyl groups, alkynyl groups, alkadienyl groups, alkadiynyl groups) having 2 to 8 carbon atoms, such as vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl, 1-heptynyl and 1-octynyl. Such alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups (e.g., cycloalkyl groups) having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; unsaturated alicyclic hydrocarbon groups (e.g., cycloalkenyl groups, cycloalkadienyl groups) having 3 to 7 carbon atoms, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and 2,4-cycloheptadienyl; and partially saturated condensed bicyclic hydrocarbon groups such as 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl and 3,4-dihydro-2-naphthyl. Such alicyclic-aliphatic hydrocarbon groups include groups resulting from the binding of one of the above-mentioned alicyclic hydrocarbon groups and one of the above-mentioned aliphatic hydrocarbon groups, and having 4 to 14 carbon atoms (e.g., C3-7 cycloalkyl-C1-4 alkyl groups, C3-7 cycloalkenyl-C1-4 alkyl groups, C3-7 cycloalkyl-C2-4 alkenyl groups, C3-7 cycloalkenyl-C2-4 alkenyl groups, C9-10 partially saturated condensed bicyclic hydrocarbon-C1-4 alkyl groups, C9-10 partially saturated condensed bicyclic hydrocarbon-C2-4 alkenyl groups) such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2-(3,4-dihydro-2-naphthyl)ethyl, 2-(1,2,3,4-tetrahydro-2-naphthyl)ethyl and 2-(3,4-dihydro-2-naphthyl)ethenyl. Such aromatic hydrocarbon groups include aryl groups having 6 to 10 carbon atoms, such as phenyl, xcex1-naphthyl, xcex2-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl and 5,6-dihydro-4-naphthyl. Such aromatic-aliphatic hydrocarbon groups include phenyl-C1-4 alkyl groups such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl and 3-phenylpropyl, aralkyl groups having 7 to 14 carbon atoms (C6-10 aryl-C1-4 alkyl groups) such as naphthyl-C1-4 alkyl groups, e.g., xcex1-naphthylmethyl, xcex1-naphthylethyl, xcex2-naphthylmethyl and xcex2-naphthylethyl, and C6-10 aryl-C2-4 alkenyl groups such as phenyl-C2-4 alkenyl groups, e.g., styryl and cinnamyl.
Said hydrocarbon group may be substituted with 1 to 3 substituents. Such substituents include, for example, lower (C1-6) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl), lower (C2-6) alkenyl groups (e.g., vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl), lower (C2-6) alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl), C3-7 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), C6-10 aryl groups (e.g., phenyl, xcex1-naphthyl, xcex2-naphthyl), aromatic heterocyclic groups [(i) aromatic 5- or 6-membered heterocyclic groups having 1 to 4 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, (ii) fused bicyclic heterocyclic groups resulting from fusion of an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and a benzene ring or an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, (iii) fused tricyclic heterocyclic groups resulting from fusion of an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, a benzene ring and an aromatic 5- or 6-membered heterocyclic ring having 1 to 3-hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms or a benzene ring, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo(4,3-a]pyridyl and 1,2,4-triazolo[4,3-b]pyridazinyl], non-aromatic heterocyclic groups (e.g., 4- to 7-membered non-aromatic heterocyclic groups having 1 to 3 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, such as oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl), C7-14 aralkyl groups (e.g., C6-10 aryl-C1-4 alkyl groups such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, xcex1-naphthylmethyl, xcex1-naphthylethyl, xcex2-naphthylmethyl and xcex2-naphthylethyl), amino groups, N-monosubstitutional amino groups [e.g., N-(C1-6 alkyl)amino groups such as methylamino, ethylamino, allylamino, cyclohexylamino and phenylamino, N-(C2-6 alkenyl)amino groups, N-(C3-7 cycloalkyl)amino groups and N-(C6-10 aryl)amino groups], N,N-disubstitutional amino groups [e.g., amino groups substituted with 2 substituents selected from C1-6 alkyl groups, C2-6 alkenyl groups, C3-7 cycloalkyl groups and C6-10 aryl groups, such as dimethylamino, diethylamino, dibutylamino, diallylamino and N-methyl-N-phenylamino], amidino groups, acyl groups (e.g., C2-8 alkanoyl groups such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonoyl, 2-cyclohexenecarbonyl, benzoyl and nicotinoyl, C3-8 alkenoyl groups, C3-7 cycloalkyl-carbonyl groups, C3-7 cycloalkenyl-carbonyl groups, C6-10 aryl-carbonyl groups, heterocyclic-carbonyl groups resulting from binding of a 5- or 6-membered aromatic or non-aromatic 5-or 6-membered heterocyclic ring having 1 to 3 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and a carbonyl group), carbamoyl groups, N-monosubstitutional carbamoyl groups, [e.g., N-(C1-6 alkyl)carbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, cyclohexylcarbamoyl and phenylcarbamoyl, N-(C2-6 alkenyl)carbamoyl groups, N-(C3-7 cycloalkyl)carbamoyl groups, N-(C6-10 aryl)carbamoyl groups], N,N-disubstitutional carbamoyl groups [e.g., carbamoyl groups substituted for by 2 substituents selected from C1-6 alkyl groups, C2-6 alkenyl groups, C3-7 cycloalkyl groups and C6-10 aryl groups, such as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, diallylcarbamoyl, N-methyl-N-phenylcarbamoyl], sulfamoyl groups, N-monosubstitutional sulfamoyl groups [e.g., N-(C1-6 alkyl)sulfamoyl groups such as methylsulfamoyl, ethylsulfamoyl, cyclohexylsulfamoyl and phenylsulfamoyl, N-(C2-6 alkenyl)sulfamoyl groups, N-(C3-7 cycloalkyl)sulfamoyl groups, N-(C6-10 aryl)sulfamoyl groups], N,N-disubstitutional sulfamoyl groups [e.g., sulfamoyl groups substituted for by 2 substituents selected from C1-6 alkyl groups, C2-6 alkenyl groups, C3-7 cycloalkyl groups and C6-10 aryl groups, such as dimethylsulfamoyl, diethylsulfamoyl, dibutylsulfamoyl, diallylsulfamoyl and N-methyl-N-phenylsulfamoyl], carboxyl groups, lower (C1-6) alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl), hydroxyl groups, lower (C1-6) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy), lower (C2-6) alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C3-7 cycloalkyloxy groups (e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy), C6-10 aryloxy groups (e.g., phenoxy, naphthyloxy), C7-14 aralkyloxy groups (e.g., C6-10 aryl-C1-4 alkyloxy groups such as phenyl-C1-4 alkyloxys and naphthyl-C1-4 alkyloxys), mercapto groups, lower (C1-6) alkylthio groups (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio), C7-14 aralkylthio groups (e.g., C6-10 aryl-C1-4 alkylthio groups such as phenyl-C1-4 alkylthios and naphthyl-C1-4 alkylthios), C6-10 arylthio groups (e.g., phenylthio, naphthylthio), lower (C1-6) alkylsulfinyl groups (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, hexylsulfinyl), C7-14 aralkylthio groups (e.g., C6-10 aryl-C1-4 alkylsulfinyl groups such as phenyl-C1-4 alkylsulfinyls and naphthyl-C1-4 alkylsulfinyls), C6-10 arylsulfinyl groups (e.g., phenylsulfinyl, naphthylsulfinyl), lower (C1-6) alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl,. isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl), C7-14 aralkylsulfonyl groups (e.g., C6-10 aryl-C1-4 alkylsulfonyl groups such as phenyl-C1-4 alkylsulfonyls and naphthyl-C1-4 alkylsulfonyls), C6-10 arylsulfonyl groups (e.g., phenylsulfonyl, naphthylsulfonyl), sulfo groups, cyano groups, azide groups, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), nitro groups, nitroso groups, phosphono groups that may be esterified [e.g., phosphono groups, (C1-6) alkoxy)phosphoryl groups such as ethoxyphosphoryl, di(C1-6 alkoxy)phosphoryl groups such as diethoxyphosphoryl], and lower (C1-6) alkyl groups substituted for by phosphono groups that may be esterified (e.g., phosphono-C1-6 alkyl groups, C1-6 alkoxyphosphoryl-C1-6 alkyl groups, di(C1-6 alkoxy)phosphoryl-C1-6 alkyl groups such as diethoxyphosphorylmethyl).
The above-mentioned C6-10 aryl groups, aromatic heterocyclic groups, C6-10 aryl groups as substituents for N-monosubstitutional amino groups, C6-10 aryl groups as substituents for N,N-disubstitutional amino groups, C6-10 aryl groups as substituents for N-monosubstitutional carbamoyl groups, C6-10 aryl groups as substituents for N,N-disubstitutional carbamoyl groups, C6-10 aryls as substituents for N-monosubstitutional sulfamoyl groups, C6-10 aryl groups as substituents for N,N-disubstitutional sulfamoyl groups, C6-10 aryl groups in C6-10 aryloxy groups, C6-10 aryl groups in C7-14 aralkyloxy groups, C6-10 aryl groups in C7-14 aralkylthio groups, C6-10 aryl groups in C6-10 arylthio groups, C6-10 aryl groups in C7-14 aralkylsulfinyl groups, C6-10 aryl groups in C7-14 aralkylsulfonyl groups, and C6-10 aryl groups in C6-10 arylsulfonyl groups may be further substituted with 1 to 3 substituents. Such substituents include, for example, lower (C1-6) alkyl groups, amino groups, N-(C1-6 alkyl)amino groups, N,N-di(C1-6 alkyl)amino groups, amidino groups, carbamoyl groups, N-(C1-6 alkyl)carbamoyl groups, N,N-di(C1-6 alkyl)carbamoyl groups, sulfamoyl groups, N-(C1-6 alkyl)sulfamoyl groups, N-N-di(C1-6 alkyl)sulfamoyl groups, carboxyl groups, lower (C2-7) alkoxycarbonyl groups, hydroxyl groups, lower (C1-6) alkoxy groups, mercapto groups, lower (C1-6) alkylthio groups, sulfo groups, cyano groups, azide groups, halogen atoms, nitro groups, nitroso groups, phosphono groups that may be esterified [e.g., phosphono groups, C1-6 alkoxyphosphoryl groups, di(C1-6 alkoxy)phosphoryl groups], and lower (C1-6) alkyl groups substituted with phosphono groups that may be esterified [e.g., phosphono-C1-6 alkyl groups, C1-6 alkoxyphosphoryl-C1-6 alkyl groups, di(C1-6 alkoxy)phosphoryl-C1-6 alkyl groups such as diethoxyphosphorylmethyl].
R2 represents a carboxyl group that may be amidated or esterified, and is exemplified by groups represented by the formula:
xe2x80x83xe2x80x94COOR3
wherein R3 represents a hydrogen atom or a hydrocarbon group that may be substituted for, and groups represented by the formula:
xe2x80x94CON(R4)(R5)
wherein R4 and R5 each represent a hydrogen atom or a hydrocarbon group that may be substituted for.
The hydrocarbon group represented by R3, R4 or R5, which may be substituted, is exemplified by the same groups as the hydrocarbon groups represented by R1 above, which may be substituted.
Ring A represents an aromatic 5-membered heterocyclic ring that may be substituted. Aromatic 5-membered heterocyclic rings include, for example, azole rings and thiophene rings that contain 1 or 2 nitrogen atoms as hetero atoms and that may contain 1 hetero atom selected from an oxygen atom and a sulfur atom, such as pyrrole rings, oxazole rings, thiazole rings, imidazole rings, pyrazole rings, isoxazole rings, isothiazole rings and thiadiazole rings.
Such thiazole rings may have 1 or 2 substituents; such substituents include, for example, the same groups as the hydrocarbon groups represented by R1 above, which may be substituted. Such thiophene rings may have 1 substituent; said substituent is exemplified by the same groups as the carboxyl groups represented by R2 above, which may be amidated or esterified. 
is preferably a group represented by 
wherein xe2x80x94pxe2x80x94qxe2x80x94rxe2x80x94represents xe2x80x94Oxe2x80x94C(A1)xe2x95x90Nxe2x80x94, xe2x80x94Sxe2x80x94C(A1)xe2x95x90Nxe2x80x94, xe2x80x94N(A2)xe2x80x94C(A1)xe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90C(A1)xe2x80x94N(A2)xe2x80x94, xe2x80x94Nxe2x95x90C(Al)xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x95x90C(A1)xe2x80x94Sxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94N(A2)xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94N(A2)xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90C(A3)xe2x80x94Sxe2x80x94; A1 and A2 each represent a hydrogen atom or a hydrocarbon group that may be substituted; A3 represents a hydrogen atom or a carboxyl group that may be amidated or esterified.
The hydrocarbon group represented by A1 or A2, which may be substituted, is exemplified by the same groups as the hydrocarbon groups represented by R1 above, which may be substituted. The carboxyl group represented by A3, which may be amidated or esterified, is exemplified by the same groups as the carboxyl groups represented by R2 above, which may be amidated or esterified.
A1 is preferably a hydrocarbon group that may be substituted; A2 is preferably a hydrogen atom; A3 is preferably a carboxyl group that may be amidated or esterified.
Regarding the compound of the present invention, represented by the general formula (I), stereoisomers or optical isomers may be present, depending on the kind of substituent; such isomers and mixtures thereof are also included in the scope of the present invention.
The salt of the compound of the present invention, represented by general formula (I), is preferably a pharmaceutically acceptable salt, exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Preferable salts with inorganic bases include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine etc. Preferable salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid etc. Preferable salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid etc. Preferable salts with basic amino acids include, for example, salts with arginine, lysine, ornithine etc. Preferable salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid etc.
Also, the salts of compounds represented by general formula (I) include the hydrates of compounds represented by general formula (I).
The compound of the present invention, represented by general formula (I), or a salt thereof, can be administered orally or non-orally, singly or as formulated with a pharmaceutically acceptable carrier, in the form of solid preparations such as tablets, capsules, granules and powders, or liquid preparations such as syrups and injectable preparations. The compound represented by general formula (I) or a salt thereof can be prepared as a pharmaceutical preparation normally wherein it is normally contained at 0.5 to 100% (w/w) by a conventional method. Pharmaceutically acceptable carriers are various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders and disintegrants for solid preparations, and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations. Other pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweetening agents may be used as necessary. Preferable excipients include, for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose and light silicic anhydride. Preferable lubricants include, for example, magnesium stearate, calcium stearate, talc and colloidal silica. Preferable binders include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyvinylpyrrolidone. Preferable disintegrants include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, crosscalmelose sodium and carboxymethyl starch sodium. Preferable solvents include, for example, water for injection, ethanol, propylene glycol, macrogol, sesame oil and corn oil. Preferable dissolution aids include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris(hydroxymethyl)aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferable suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and monostearic glycerol; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferable isotonizing agents include, for example, sodium chloride, glycerol and D-mannitol. Preferable buffers include, for example, buffer solutions of phosphates, acetates, carbonates, citrates etc. Preferable soothing agents include, for example, benzyl alcohol. Preferable preservatives include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Preferable antioxidants include, for example, sulfites and ascorbic acid.
The present invention further provides a method of producing a compound represented by general formula (I) or a salt thereof. In the reactions below, when the starting compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups may incorporate a protecting group in common use in peptide chemistry and other fields; the desired compound can be obtained by removing the protecting group after reaction as necessary. Useful amino group-protecting groups include, for example, C1-6 alkanoyls that may be substituted (e.g., formyl, acetyl, propionyl, butyryl), benzoyl, C2-6 alkoxycarbonyls (e.g., methoxycarbonyl, ethoxycarbonyl), phenoxycarbonyls, C7-14 aralkyloxycarbonyls (e.g., phenyl-C2-4 alkoxycarbonyls such as benzyloxycarbonyl), trityl and phthaloyl. Substituents for these protecting groups include, for example, halogen atoms (e.g., fluorine, chorine, bromine, iodine), C1-6 alkanoyls (e.g., formyl, acetyl, propionyl, butyryl) and nitro groups, the number of substituents being about 1 to 3. Useful carboxyl group-protecting groups include, for example, C1-6 alkyls that may have a substituent (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl and silyl. Substituents for these protecting groups include, for example, halogen atoms (e.g., fluorine, chorine, bromine, iodine), C1-6 alkanoyls (e.g., formyl, acetyl, propionyl, butyryl) and nitro groups, the number of substituents being about 1 to 3. Useful hydroxyl group-protecting groups include, for example, C1-6 alkyls that may have a substituent (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, C7-14 aralkyls (e.g., phenyl-C1-4 alkyls such as benzyl), C1-6 alkanoyls (e.g., formyl, acetyl, propionyl, butyryl), phenoxycarbonyl, C7-14 aralkyloxycarbonyls (e.g., phenyl-C2-4 alkoxycarbonyls such as benzyloxycarbonyl), pyranyl, furanyl and silyl. Substituents for these protecting groups include, for example, halogen atoms (e.g., fluorine, chorine, bromine, iodine), C1-6 alkyls, phenyls, C7-14 aralkyls (e.g., benzyl) and nitro groups, the number of substituents being about 1 to 4. Protecting group introduction and removal can be achieved by commonly known methods or methods based thereon [e.g., method described in Protective Groups in Organic chemistry, J.F.W. McOmie et al., Prenam Press)].
[Method A]
[In the above formulas, R6 represents a hydrocarbon group that corresponds to R3 and that may be substituted; Hal represents a halogen atom (e.g., fluorine, chlorine, bromine, iodine); Q represents a sulfur atom, an oxygen atom or an NH group; the other symbols have the same definitions as those shown above.]
In this method, a compound represented by general formula (1) is first halogenated to compound (2) by a commonly known method, then reacted with an amide, thioamide or amidine represented by general formula (3) to yield compound (4). The reaction of compounds (2) and (3) is carried out in an appropriate solvent in the presence or absence of a base. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate and mixtures thereof. Said base is exemplified by bases selected as appropriate from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as soidum hydride and potassium hydride, and amines such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine and N,N-dimethylaniline. The amount of base used is preferably about 0 to about 5 mol equivalents per mol equivalent of compound (2); the amount of amide or thioamide, amidine (3) used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (2). This reaction is normally carried out at about 0C. to about +180xc2x0 C., preferably about +30xc2x0 C. to +120xc2x0 C., over a period of about 30 minutes to about 50 hours. Compound (4) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (4) wherein R2 is xe2x80x94COOR6 [i.e., compound (4xe2x80x2)] to a commonly known acid or alkali hydrolysis reaction, corresponding carboxylic acid (5) can be produced; also, by subjecting compound (5) to a commonly known amidation reaction [reaction with compound (6)], compound (7) can be produced. Said amidation reaction can be carried out by reacting compound (5) with compound (6) after being converted to an acid halide with a halogenating agent such as oxalyl chloride or thionyl chloride. The reaction of compound (5) and halogenating agent is normally carried out in a solvent. Said solvent is exemplified by aromatic hydrocarbons such as benzene and toluene, and ethers such as diethyl ether and tetrahydrofuran. As a reaction promoter, pyridine, N,N-dimethylformamide, or the like, for example, may be used. This reaction is normally carried out at about 0xc2x0 C. to about +120xc2x0 C. over a period of about 30 minutes to about 24 hours. The amount of halogenating agent used is preferably about 1 to 2 mol equivalents per mol equivalent of compound (5). The acid halide thus obtained may be subjected to a reaction with compound (6) after being separated by an ordinary means of separation and purification. Alternatively, the reaction mixture, containing said acid halide, may be subjected to a reaction with compound (6) without separation. The reaction of acid halide and compound (6) is normally carried out in a solvent. Said solvent is exemplified by halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, dioxane and tetrahydrofuran, acetone, acetonitrile, ethyl acetate and N,N-dimethylformamide. Also, the reaction may be carried out using an excess amount of compound (6) as a solvent. This reaction can be carried out in the presence or absence of a base. Said base is exemplified by organic bases such as trimethylamine, triethylamine, pyridine and N,N-dimethylaniline, and inorganic bases such as sodium hydrogen carbonate and potassium carbonate. Although the amount of compound (6) used is preferably about 1 to 2 mol equivalents per mol equivalent of acid halide, an excess amount of compound (6) may be used as a solvent. This reaction is normally carried out at about 0xc2x0 C. to about +120xc2x0 C. over a period of about 30 minutes to about 24 hours.
Compound (4) wherein Y is S can also be converted to compound (4) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out by reacting compound (4) wherein Yis S with a peracid such as m-chloroperbenzoic acid or peracetic acid. This reaction is normally carried out in a solvent. Said solvent is exemplified by halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,1,2,2-tetrachloroethane. By using a peracid at about 1 mol equivalent per mol equivalent of compound (4) wherein Y is S, compound (4) wherein Y is SO can be produced. This reaction is normally carried out at about xe2x88x9230xc2x0 C. to about +10xc2x0 C. over a period of about 30 minutes to about 24 hours. By using a peracid at about 2 mol equivalents per mol equivalent of compound (4) wherein Y is S, compound (4) wherein Y is SO2 can be produced. This reaction is normally carried out at about 0xc2x0 C. to about +50xc2x0 C. over a period of about 30 minutes to about 24 hours.
Of the compounds represented by general formula (4), those wherein Q is an NH group can be isomerized as represented by general formulas (4-1) and (4-2), which isomers may be subjected to a reaction with a halogenated hydrocarbon represented by general formula (8) to yield compounds (9-1) and (9-2). This reaction is carried out in an appropriate solvent in the presence or absence of a base. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and mixtures thereof. Said base is exemplified by bases selected as appropriate from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as sodium hydride and potassium hydride, and amines such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine and N,N-dimethylaniline. The amount of base used is preferably about 0 to about 5 mol equivalents per mol equivalent of compound (4); the amount of halogenated hydrocarbon (8) used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (4). This reaction is normally carried out at about 0xc2x0 C. to about +180xc2x0 C., preferably about +30xc2x0 C. to +120xc2x0 C., over a period of about 30 minutes to about 50 hours. Compounds (9-1) and (9-2) thus obtained may each be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[Method B]
(In the above formulas, the symbols have the same definitions as those shown above.)
In this method, compound (12) is produced by azidating a compound represented by general formula (2) above by a commonly known method to yield compound (10), which is then reduced in the presence of a great excess of lower carboxylic anhydride (11) (e.g., acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride). Said reduction reaction is preferably catalytic reduction using a transition metal catalyst (e.g., palladium, platinum, rhodium) and hydrogen. Also, this reaction is carried out in a solvent that does not adversely affect the reaction. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, ethyl acetate, lower carboxylic acids corresponding to acid anhydride (11) (e.g., acetic acid, propionic acid, butyric acid, isobutyric acid) and mixtures thereof. Reaction temperature is normally about xe2x88x9220xc2x0 C. to about +150xc2x0 C., preferably about 0xc2x0 C. to about +100xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (12) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (12) to a reaction with phosphorus oxychloride in an appropriate solvent or in the absence of a solvent, compound (13) is produced. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethyl sulfoxide, acetonitrile and mixtures thereof. The amount of phosphorus oxychloride used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (12); Reaction temperature is normally about 0xc2x0 C. to about +150xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (13) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (13) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (13) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (13) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (13) wherein R2 is xe2x80x94CONR4R5 can be produced. This reaction can be carried out under the same conditions as those for the reaction of compound (4xe2x80x2) to compound (5) and the reaction of compound (5) to compound (7).
Compound (13) wherein Y is S can also be converted to compound (13) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
[Method C]
(In the above formulas, R7 represents a methyl group or an ethyl group; the other symbols have the same definitions as those shown above.)
In this method, compound (14) is produced by reducing a compound represented by general formula (10) above. Said reduction reaction is preferably catalytic reduction using a transition metal catalyst (e.g., palladium, platinum, rhodium) and hydrogen. Also, this reaction is carried out in a solvent that does not adversely affect the reaction. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, N,N-dimethylformamide, ethyl acetate and mixtures thereof. Reaction temperature is normally about xe2x88x9220xc2x0 C. to about +150xc2x0 C., preferably about 0xc2x0 C. to about +100xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (14) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (14) to a reaction with a dithio ester represented by general formula (15) in an appropriate solvent or in the absence of a solvent, compound (16) is produced. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and mixtures thereof. The amount of dithio ester (15) used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (14). Reaction temperature is normally about 0xc2x0 C. to about +150xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (16) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By reacting compound (16) with phosphorus oxychloride in the same manner as method B, compound (17) is produced.
By subjecting compound (17) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (17) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (17) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (17) wherein R2 is xe2x80x94CONR4R5 can be produced. This reaction can be carried out under the same conditions as those for the reaction of compound (4xe2x80x2) to compound (5) and the reaction of compound (5) to compound (7).
Compound (17) wherein Y is S can also be converted to compound (17) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
[Method D]
(In the above formulas, Qxe2x80x2 represents an oxygen atom or NA1; the other symbols have the same definitions as those shown above.)
In this method, compound (18) is produced by subjecting a compound represented by general formula (1) above to a reaction with phosphorus oxychloride in N,N-dimethylformamide. Useful solvents include, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane and mixtures thereof. The amount of phosphorus oxychloride used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (1). Reaction temperature is normally about xe2x88x9220xc2x0 C. to about +180xc2x0 C., preferably about 0xc2x0 C. to about +120xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (18) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
Compound (20) is produced by a reaction of compound (18) and a hydroxylamine or hydrazine represented by general formula (19). This reaction is advantageously carried out in a solvent that does not adversely affect the reaction in the presence of a base. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and mixtures thereof. Said base is exemplified by bases selected as appropriate from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as sodium hydride and potassium hydride, and amines such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine and N,N-dimethylaniline. The amount of base used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (18); the amount of hydroxylamine or hydrazine (19) used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (18). This reaction is normally carried out at about 0xc2x0 C. to about +180xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., over a period of about 30 minutes to about 50 hours. Compound (20) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (20) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (20) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (20) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (20) wherein R2 is xe2x80x94CONR4R5 can be produced. This reaction can be carried out under the same conditions as those for the reaction of compound (4xe2x80x2) to compound (5) and the reaction of compound (5) to compound (7).
Compound (20) wherein Y is S can also be converted to compound (20) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
[Method E]
(In the above formulas, the symbols have the same definitions as those shown above.)
In this method, compound (21) is produced by subjecting a compound represented by general formula (18) above to a reaction with sulfur and sodium sulfide in an appropriate solvent and subsequently treating it with sulfuryl chloride. Said solvent is exemplified by ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and mixtures thereof. The amounts of sulfur and sodium sulfide used are each preferably about 1 to about 3 mol.equivalents per mol equivalent of compound (18). Reaction temperature is normally about 0xc2x0 C. to about +180xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., reaction time being about 1 hour to about 24 hours. The sulfuryl chloride treatment of the intermediate thus obtained is carried out in a solvent that does not adversely affect the reaction. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane and mixtures thereof. The amount of sulfuryl chloride used is preferably about 1 to about 3 mol equivalents per mol equivalent of compound (18). Reaction temperature is normally about xe2x88x9220xc2x0 C. to about +150xc2x0 C., preferably about 0xc2x0 C. to about +100xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (21) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
Compound (22) is produced by a reaction of compound (21) and a great excess of ammonia. This reaction is carried out in a solvent that does not adversely affect the reaction. Said solvent is exemplified by ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol and mixtures thereof. This reaction is normally carried out at about xe2x88x9220xc2x0 C. to about +180xc2x0 C., preferably about 0xc2x0 C. to about +120xc2x0 C., over a period of about 1 hour to about 50 hours. Compound (22) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (22) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (22) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (22) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (22) wherein R2 is xe2x80x94CONR4R5 can be produced. This reaction can be carried out under the same conditions as those for the reaction of compound (4xe2x80x2) to compound (5) and the reaction of compound (5) to compound (7).
Compound (22) wherein Y is S can also be converted to compound (22) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
[Method F]
(In the above formulas, R8 represents an ethoxycarbonyl group or a p-toluenesulfonyl group; the other symbols have the same definitions as those shown above.)
In this method, compound (24) is produced by subjecting a compound represented by general formula (1) above to a reaction with ethyl carbazinate or p-toluenesulfonyl hydrazide represented by general formula (23) in an appropriate solvent. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate and mixtures thereof. The amount of ethyl carbazinate or p-toluenesulfonyl hydrazide (23) used is preferably about 1 to about 2 mol equivalents per mol equivalent of compound (1). Reaction temperature is normally about 0xc2x0 C. to about +180xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (24) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
Compound (25) is produced by treating compound (24) with thionyl chloride. This reaction is carried out in an appropriate solvent or in the absence of a solvent. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane and mixtures thereof. This reaction is normally carried out at about xe2x88x9220xc2x0 C. to about +180xc2x0 C., preferably about 0xc2x0 C. to about +120xc2x0 C., over a period of about 1 hour to about 50 hours. Compound (25) thus obtained may be isolated and purified by known means or separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (25) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (25) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (25) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (25) wherein R2 is xe2x80x94CONR4R5 can be produced. This reaction can be carried out under the same conditions as those for the reaction of compound (4xe2x80x2) to compound (5) and the reaction of compound (5) to compound (7).
Compound (25) wherein Y is S can also be converted to compound (25) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
[Method G]
(In the above formulas, the symbols have the same definitions as those shown above.)
In this method, compound (27) is produced by subjecting a compound represented by general formula (18) above to a reaction with a thiol represented by general formula (26) in an appropriate solvent in the presence of a base. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate and mixtures thereof. Said base is exemplified by bases selected as appropriate from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as sodium hydride and potassium hydride, and amines such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine and N,N-dimethylaniline. The amount of base used is preferably about 1 to about 5 mol equivalents per mol equivalent of compound (18); the amount of thiol (26) used is preferably about 1 to about 3 mol equivalents per mol equivalent of compound (18). This reaction is normally carried out at about 0xc2x0 C. to about +180xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., over a period of about 1 hour to about 50 hours. Compound (27) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
Although compound (28) may be produced partially in the above reaction, it is normally produced by subjecting compound (27) to an aldol type dehydration condensation reaction. This reaction is carried out in a solvent that does not adversely affect the reaction. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, acetonitrile, ethyl acetate and mixtures thereof. Said dehydrating agent is selected as appropriate from lower carboxylic anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride and isobutyric anhydride, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and mixtures of amines (pyrrolidine, piperidine etc.) and carboxylic acids (acetic acid, benzoic acid etc.). The amount of dehydrating agent used is a catalytic amount to great excess, relative to compound (27); reaction temperature is normally about 0xc2x0 C. to about +180xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., reaction time being about 1 hour to about 50 hours. Compound (28) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (28) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (28) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (28) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (28) wherein R2 is xe2x80x94CONR4R5 can be produced. This reaction can be carried out under the same conditions as those for the reaction of compound (4xe2x80x2) to compound (5) and the reaction of compound (5) to compound (7).
Compound (28) wherein Y is S can also be converted to compound (28) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
[Method H]
(In the above formulas, the symbols have the same definitions as those shown above.)
In this method, compound (30) is produced by subjecting a compound represented by general formula (2) above to a reaction with an imine represented by general formula (29) in an appropriate solvent in the presence of a base. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane and mixtures thereof. Said base is exemplified by bases selected as appropriate from lithium diethylamide and lithium diisopropylamide. The amount of base used is preferably about 1 to about 2 mol equivalents per mol equivalent of compound (2); the amount of imine (29) used is preferably about 1 to about 2 mol equivalents per mol equivalent of compound (2). This reaction is advantageously carried out by first treating imine (29) with a base and subsequently adding compound (2). Reaction temperature is normally about xe2x88x9280xc2x0 C. to about +100xc2x0 C., preferably about xe2x88x9280xc2x0 C. to about +30xc2x0 C., reaction time being about 30 minutes to about 24 hours. Compound (30) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (30) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (30) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (30) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (30) wherein R2 is xe2x80x94CONR4R5 can be produced. This reaction can be carried out under the same conditions as those for the reaction of compound (4) to compound (5) and the reaction of compound (5) to compound (7).
Compound (30) wherein Y is S can also be converted to compound (30) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
Regarding starting compound (1) for methods A through H, a compound known in the literature [Synthetic Communications, Vol. 25, p. 2,449 (1995); Journal of Medicinal Chemistry, Vol. 39, p. 398 (1996)] may be used as such, or it can be synthesized by the methods described therein or methods based thereof.
Of the compounds represented by general formula (1), those wherein X is a sulfur atom, for example, can be produced by method I below.
[Method I]
(In the above formulas, the symbols have the same definitions as those shown above.)
In this method, 1,3-cyclohexanedione is first treated with a base, carbon disulfide and halogenated hydrocarbon (31) in that order to yield a dithio ester represented by general formula. (32). This reaction is carried out in a solvent that does not adversely affect the reaction. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and mixtures thereof. Said base is exemplified by bases selected as appropriate from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as sodium hydride and potassium hydride, and amines such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine and N,N-dimethylaniline. The amount of base used is preferably about 1 to about 2 mol equivalents per mol equivalent of 1,3-cyclohexanedione; the amount of carbon disulfide used is preferably about 1 to about 2 mol equivalents per mol equivalent of 1,3-cyclohexanedione; the amount of halogenated hydrocarbon (31) used is preferably about 1 to about 2mol equivalents, particularly about 1 mol equivalent, per mol equivalent of 1,3-cyclohexanedione. This reaction is normally carried out at about xe2x88x9280xc2x0 C. to about +150xc2x0 C., preferably about xe2x88x9220xc2x0 C. to +100xc2x0 C., over a period of about 1 hour to about 24 hours. Compound (32) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
Compound (1) is produced by subjecting compound (32) to a reaction with an ester represented by general formula (33) in an appropriate solvent in the presence of a base. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate and mixtures thereof. Said base is exemplified by bases selected as appropriate from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as sodium hydride and potassium hydride, and amines such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine and N,N-dimethylaniline. The amount of base used is preferably about 1 to about 10 mol equivalents, particularly about 1 to about 5 mol equivalents, per mol equivalent of compound (32); the amount of ester (33) used is preferably about 1 to about 2 mol equivalents per mol equivalent of compound (32). Reaction temperature is normally about 0xc2x0 C. to about +180xc2x0 C., preferably about +30xc2x0 C. to about +120xc2x0 C., reaction time being about 1 hour to about 24 hours. Compound (1) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (1) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (1) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (1) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (1) wherein R2 is xe2x80x94CONR4R5 can be produced.
Compound (1) wherein Y is S can also be converted to compound (1) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
Of the compounds represented by general formula (1), those wherein X is an oxygen atom can be produced by method J below.
[Method J]
(In the above formulas, the symbols have the same definitions as those shown above.)
In this method, 1,3-cyclohexanedione is first treated with a base, carbon disulfide and halogenated hydrocarbon (31) in an appropriate solvent to yield a dithio acetal represented by general formula (34). Said solvent and base are selected as appropriate from the solvents and bases used to produce compound (32) by method I above. The amount of base used is preferably about 1 to about 5 mol equivalents, particularly about 2 to about 3 mol equivalents, per mol equivalent of 1,3-cyclohexanedione; the amount of carbon disulfide used is preferably about 1 to about 5 mol equivalents, particularly about 1 to about 2 mol equivalent, per mol equivalent of 1,3-cyclohexanedione; the amount of halogenated hydrocarbon (31) used is preferably about 2 to about 5 mol equivalents, particularly about 2 to about 3 mol equivalent, per mol equivalent of 1,3-cyclohexanedione. This reaction is normally carried out at about xe2x88x9280xc2x0 C. to about +150xc2x0 C., preferably about xe2x88x9220xc2x0 C. to +100xc2x0 C., over a period of about 1 hour to about 24 hours. Compound (34) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
Compound (1) is produced by subjecting compound (34) to a reaction with an ester represented by general formula (33) in an appropriate solvent in the presence of a base, and subsequently treating it with an acid. Said solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane and mixtures thereof. Said base is exemplified by bases selected as appropriate from lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. The amount of base used is preferably about 1 to about 2 mol equivalents per mol equivalent of compound (34); the amount of ester (33) used is preferably about 1 to about 2 mol equivalents per mol equivalent of compound (34). Reaction temperature is normally about xe2x88x9280xc2x0 C. to about +100xc2x0 C., preferably about xe2x88x9280xc2x0 C. to about +50xc2x0 C., reaction time being about 1 hour to about 24 hours. The acid treatment of the intermediate thus obtained is carried out in a solvent that does not adversely affect the reaction. When the acid used is an inorganic mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, useful solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, acetonitrile, water and mixtures thereof. The amount of acid used is normally great excess. Reaction temperature is normally about 0xc2x0 C. to about +150xc2x0 C., preferably about +30xc2x0 C. to about +100xc2x0 C., reaction time being about 30 minutes to about 10 hours. When the acid used is a Lewis acid such as a boron trihalide (e.g., boron trichloride, boron trifluoride), an aluminum trihalide (e.g., aluminum chloride, aluminum bromide), a titanium tetrahalide (e.g., titanium tetrachloride, titanium tetrabromide) or a tin tetrahalide (e.g., tin tetrachloride, tin tetrabromide), useful solvents include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane and mixtures thereof. The amount of acid used is a catalytic amount to about 5 mol equivalents, preferably about 1 to about 2 mol equivalents, per mol equivalent of compound (34). Reaction temperature is normally about xe2x88x9230xc2x0 C. to about +100xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about +50xc2x0 C., reaction time being about 30 minutes to about 10 hours. Compound (1) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
By subjecting compound (1) wherein R2 is xe2x80x94COOR6 to a commonly known acid or alkali hydrolysis reaction, compound (1) wherein R2 is xe2x80x94COOH can be produced. Also, by subjecting compound (1) wherein R2 is xe2x80x94COOH to a commonly known amidation reaction [reaction with compound (6)], compound (1) wherein R2 is xe2x80x94CONR4R5 can be produced.
Compound (1) wherein Y is S can also be converted to compound (1) wherein Y is SO or SO2 by a commonly known oxidation reaction. This reaction can be carried out under the same conditions as those for the reaction of compound (4) wherein Y is S to compound (4) wherein Y is SO or SO2.
A compound represented by general formula (I) wherein ring A is an aromatic 5-membered heterocyclic ring that may be substituted for, and which is other than the above-mentioned ones, or a salt thereof, can also be produced in the same manner as the above-described methods.
Compound (I) or its salt as obtained by the above-described methods may be a hydrate or not.
The cell differentiation inducing factors serving as targets of the present invention include factors that induce a character of the process of differentiation of undifferentiated precursor cells that maintain living body function in particular tissue, such as osteoblasts and nerve cells, e.g., factors belonging to the TGF-xcex2 superfamily such as bone morphogenetic protein (BMP), neurotrophic factor, glial cell line-derived neurotropin factor (GDNF), tumor growth factor (TGF)-xcex2 and activin, factors belonging to the FGF superfamily such as basic fibroblast growth factor (bFGF) and acidic fibroblast growth factor (aFGF), factors belonging to the neuropoietic cytokine family such as leukocyte inhibition factor (LIF, or also called CDF) and ciliary neurotrophic factor (CNTF), interleukin (IL)-1, IL-2, IL-3, IL-5, IL-6, IL-7, IL-9, IL-11, tumor necrosis factor (TNF)-xcex1 and interferon (IFN)-xcex3, with preference given to BMP and neurotrophic factor. Examples of BMP include members of the BMP family of proteins that promote osteogenesis and chondrogenesis, such as BMP2, BMP4, BMP5, BMP6, BMP7, BMP8, BMP9, BMP10, BMP11 and BMP12, with preference given to BMP2, BMP4, BMP6 and BMP7. BMP may be a homo-dimer of each of the above-mentioned factors or a hetero-dimer consisting of any possible combination thereof. Neurotrophic factors include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophine-3 (NT-3), with preference given to the NGF family. The cell differentiation induction factor action enhancer of the present invention, containing a compound represented by general formula (I) or a salt thereof, can be used to treat and prevent various bone diseases such as bone fractures and osteoporosis, and to treat and prevent nerve degeneration diseases in cerebral vascular dementia, senile dementia, Alzheimer""s disease, etc., amyotrophic lateral sclerosis (Lou Gehrig disease) and various diseases based on cerebral dysfunction or nerve degeneration such as depression and diabetic peripheral neuropathy. In addition, the compound of the present invention, represented by general formula (I), or a salt thereof, is expected to serve as a therapeutic drug and prophylactic drug for diseases wherein the pathologic condition is improved by enhancement of these actions by BMP, neurotrophic factor, etc., in addition to the above-described roles thereof invivo. Also, the compound of the present invention, represented by general formula (I), or a salt thereof, possesses anti-matrix metalloprotease activity; including anti-collagenase activity, and can be used to treat and prevent osteoarthritis. Varying depending on patient condition and body weight and method of administration, the daily dose of the compound of the present invention, represented by general formula (I), or a salt thereof, is normally about 5 to about 1,000 mg, preferably about 10 to about 600 mg, and more preferably about 15 to about 150 mg, per day, based on the active ingredient [compound of the present invention, represented by general formula (I), or a salt thereof], per adult (weight 50 kg), administered in 1 to 3 portions per day. The compound represented by general formula (I) or a salt thereof is of low toxicity.
The compound of the present invention, represented by general formula (I), or a salt thereof, can be mixed in a carrier for bone reconstruction as an osteogenesis promoter in bone repair and bone transplantation because it possesses potent osteogenesis-promoting activity. For example, the compound represented by general formula (I) or a salt thereof can be used as adhered to, or contained in, artificial bones etc. prepared from metals, ceramics or high-molecular substances. The artificial bone is preferably made porous on the surface thereof to allow the effective release of the compound of the present invention, represented by general formula (I), or a salt thereof, in the living tissue upon its transplantation to a bone defect. The compound of the present invention, represented by general formula (I), or a salt thereof, can be adhered to, or contained in, an artificial bone by dispersing it in an appropriate dispersant, binder, diluent or the like (e.g., collagen, physiological saline, citric acid solution, acetic acid solution, hydroxyapatite, fibrin, mixture thereof) and applying it to, or impregnating it in, the artificial bone. Such artificial bone is transplanted to a bone defect and firmly fixed to the defect. An artificial bone fixative can be prepared by mixing the active ingredient [compound represented by general formula (I) or a salt thereof] with pharmaceutically acceptable dispersants, binders, diluents, other components effective on bone regeneration (e.g., calcium), etc. The artificial bone fixative can also be used as filled in the gap between the artificial bone transplanted to the bone defect in the host and the bone defect, without adhering it to, or containing it in, the artificial bone. It should also be noted that the non-oral composition described here can also be used with an osteogenesis-promoting protein such as the BMP family adhered thereto or contained therein.
The compound of the present invention, represented by general formula (I), or a salt thereof, possesses potent activity of enhancing cell differentiation inducing factor action and anti-matrix metalloprotease activity, and can be advantageously used in the treatment and prevention of various metabolic bone diseases such as osteoporosis, bone fractures, diseases based on nerve degeneration, and diseases such as osteoarthritis, rheumatoid arthritis, arteriosclerosis and cancer metastasis, in mammals (e.g., humans, mice, rats, rabbits, cats, dogs, bovines, pigs).